B cell-specific knockout of AID protects against atherosclerosis.

Antigen-naive IgM-producing B cells are atheroprotective, whereas mature B cells producing class-switched antibodies promote atherosclerosis. Activation-induced cytidine deaminase (AID), which mediates class switch recombination (CSR), would thus be expected to foster atherosclerosis. Yet, AID also plays a major role in the establishment of B cell tolerance.

Design and development of Branched Poly(ß-aminoester) nanoparticles for Interleukin-10 gene delivery in a mouse model of atherosclerosis.

Atherosclerosis progression is a result of chronic and non-resolving inflammation, effective treatments for which still remain to be developed. We designed and developed branched poly(ß-amino ester) nanoparticles (NPs) containing plasmid DNA encoding IL-10, a potent anti-inflammatory cytokine to atherosclerosis. The NPs (NP-VHPK) are functionalized with a targeting peptide (VHPK) specific for VCAM-1, which is overexpressed by endothelial cells at sites of atherosclerotic plaque.

MNK2 governs the macrophage antiinflammatory phenotype.

Tumor-associated macrophages (TAMs) continuously fine tune their immune modulatory properties, but how gene expression programs coordinate this immune cell plasticity is largely unknown. Selective mRNA translation, controlled by MNK1/MNK2 and mTOR pathways impinging on eIF4E, facilitates reshaping of proteomes without changes in abundance of corresponding mRNAs. Using polysome profiling developed for small samples we show that, during tumor growth, gene expression in TAMs is predominately modulated via mRNA-selective changes in translational efficiencies.

FHL2 Is Essential for Spleen T Cell-Dependent B Cell Activation and Antibody Response.

Four-and-a-half LIM domain protein 2 (FHL2) is an adaptor molecule regulating various cellular processes, including signal transduction, transcription, and cell survival. Although involved in inflammation and immune responses, its role in the germinal center reaction and B cell maturation remains unknown. We found that FHL2 mouse spleens displayed enlarged follicles with more B cells.

Matrix metalloproteinase-2 knockout prevents angiotensin II-induced vascular injury.

Aims: Matrix metalloproteinases (MMPs) have been implicated in the development of hypertension in animal models and humans. Mmp2 deletion did not change Ang II-induced blood pressure (BP) rise. However, whether Mmp2 knockout affects angiotensin (Ang) II-induced vascular injury has not been tested.

Gas6 Promotes Inflammatory (CCR2CX3CR1) Monocyte Recruitment in Venous Thrombosis.

Objective: Coagulation and inflammation are inter-related. Gas6 (growth arrest-specific 6) promotes venous thrombosis and participates to inflammation through endothelial-innate immune cell interactions. Innate immune cells can provide the initiating stimulus for venous thrombus development.

Absence of Four-and-a-Half LIM Domain Protein 2 Decreases Atherosclerosis in ApoE-/- Mice.

Objective: Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial cells, vascular smooth muscle cells, and leukocytes. It regulates cell survival, migration, and inflammatory response, but its role in atherogenesis is unknown.

Approach And Results: To investigate the role of FHL2 in atherosclerosis, FHL2-deficient mice were crossed with ApoE-deficient mice, to generate ApoE/FHL2-/- mice.

Inhibition of four-and-a-half LIM domain protein-2 increases survival, migratory capacity, and paracrine function of human early outgrowth cells through activation of the sphingosine kinase-1 pathway: implications for endothelial regeneration.

Rationale: Inhibition of four-and-a-half LIM domain protein-2 (FHL2) attenuates atherosclerotic lesion formation and increases endothelial cell migration. Early outgrowth cells (EOCs) contribute substantially to endothelial repair.

Objective: We investigated the role of FHL2 in the regulation of EOCs.

Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease.

Aims: Vascular peroxisome proliferator-activated receptor γ (PPARγ) activation improves vascular remodelling and endothelial function in hypertensive rodents. The goal of this study was to determine that vascular smooth muscle cell (VSMC) PPARγ exerts a vascular protective role beyond its metabolic effects.

Methods And Results: We generated a model of adult inducible VSMC-specific Pparγ inactivation to test the hypothesis that PPARγ counteracts angiotensin (Ang) II-induced vascular remodelling and endothelial dysfunction.

Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration.

Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood.

Inactivation of endothelial proprotein convertase 5/6 decreases collagen deposition in the cardiovascular system: role of fibroblast autophagy.

Proprotein convertase (PC) 5/6 belongs to a family of secretory proteases involved in proprotein proteolysis. Several studies suggest a role for PC5/6 in cardiovascular disease. Because lethality at birth of mice lacking PC5/6 precluded elucidation of its function in the adult, we generated mice in which the gene of PC5/6 (pcsk5) is specifically inactivated in endothelial cells (ecKO), which are viable and do not exhibit overt abnormalities.

Antiproliferative effect of estrogen in vascular smooth muscle cells is mediated by Kruppel-like factor-4 and manganese superoxide dismutase.

The mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) and the zinc finger transcription factor Kruppel-like factor-4 (KLF4) are involved in the regulation of redox homeostasis, apoptosis and cell proliferation. We have shown that estrogen exerts antioxidative actions via induction of MnSOD in cultured rat aortic vascular smooth muscle cells (VSMC). The purpose of the present study was to investigate whether estrogen inhibits VSMC proliferation via alteration of KLF4 and MnSOD expression.

Mitogen-activated protein kinase-activated protein kinase 2 in angiotensin II-induced inflammation and hypertension: regulation of oxidative stress.

Vascular oxidative stress and inflammation play an important role in angiotensin II-induced hypertension, and mitogen-activated protein kinases participate in these processes. We questioned whether mitogen-activated protein kinase-activated protein kinase 2 (MK2), a downstream target of p38 mitogen-activated protein kinase, is involved in angiotensin II-induced vascular responses. In vivo experiments were performed in wild-type and Mk2 knockout mice infused intravenously with angiotensin II.

Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1.

In the present study, we tested the hypothesis that the PPARgamma (peroxisome-proliferator-activated receptor gamma) activator rosiglitazone improves vascular structure and function in aged hyperhomocysteinaemic MTHFR (methylene tetrahydrofolate reductase) gene heterozygous knockout (mthfr+/-) mice fed a HCD (high-cholesterol diet), a model of high cardiovascular risk. One-year-old mthfr+/- mice were fed or not HCD (6 mg x kg-1 of body weight x day-1) and treated or not with rosiglitazone (20 mg x kg-1 of body weight x day-1) for 90 days and compared with wild-type mice. Endothelium-dependent relaxation of carotid arteries was significantly impaired (-40%) only in rosiglitazone-treated HCD-fed mthfr+/- mice.

Endothelial nitric oxide synthase uncoupling and perivascular adipose oxidative stress and inflammation contribute to vascular dysfunction in a rodent model of metabolic syndrome.

The metabolic syndrome represents a constellation of cardiovascular risk factors that promote the development of cardiovascular disease. Oxidative stress is a mediator of endothelial dysfunction and vascular remodeling. We investigated vascular dysfunction in the metabolic syndrome and the oxidant mechanisms involved.

Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors.

Rationale: Aldosterone has been shown to induce vascular damage, endothelial dysfunction, and myocardial fibrosis, which depend in part on activation of angiotensin II (Ang II)-mediated pathways. However, mechanisms underlying crosstalk between Ang II type 1 receptor (AT(1)R) and mineralocorticoid receptor (MR) are mostly unknown.

Objectives: We tested whether the lack of Ang II type 1a receptor (AT(1a)R) or Ang II type 1b receptor (AT(1b)R) would decrease cellular effects induced by aldosterone.

Aldosterone induces arterial stiffness in absence of oxidative stress and endothelial dysfunction.

Aims: Monocyte/macrophages participate in inflammatory responses that may play an important role in mineralocorticoid-induced vascular damage. We hypothesized that monocyte/macrophages modulate aldosterone effects on oxidative stress, endothelial function, and ultimately vascular stiffness.

Methods: Adult heterozygous osteopetrotic (Op/+) and wild-type mice were infused with aldosterone (600 microg/kg per day s.

Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause.

Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model.

Thioredoxin in vascular biology: role in hypertension.

The thioredoxin (TRX) system consists of TRX, TRX reductase, and NAD(P)H, and is able to reduce reactive oxygen species (ROS) through interactions with the redox-active center of TRX, which in turn can be reduced by TRX reductase in the presence of NAD(P)H. Among the TRX superfamily is peroxiredoxin (PRX), a family of non-heme peroxidases that catalyzes the reduction of hydroperoxides into water and alcohol. The TRX system is active in the vessel wall and functions either as an important endogenous antioxidant or interacts directly with signaling molecules to influence cell growth, apoptosis, and inflammation.

Differential regulation of thioredoxin and NAD(P)H oxidase by angiotensin II in male and female mice.

Objective: We hypothesized that downregulation of the antioxidant thioredoxin system contributes to oxidative stress in angiotensin II-induced hypertension. As oestrogen may protect against oxidative stress, we also evaluated whether the thioredoxin system, particularly in the heart, is differentially regulated between females and males.

Results: C57Bl/6 male and intact or ovariectomized female mice were infused with angiotensin II (400 ng/kg per minute for 2 weeks).

Angiotensin II/AT2 receptor-induced vasodilation in stroke-prone spontaneously hypertensive rats involves nitric oxide and cGMP-dependent protein kinase.

Background: Angiotensin II (Ang II) induces vasodilation, in part, through angiotensin type 2 receptor (AT2R)-induced actions in conditions associated with angiotensin type 1 receptor (AT1R) blockade and AT2R upregulation. Ang II/AT2R-induced vasodilation involves nitric oxide (NO)-cyclic guanosine monophosphate (cGMP)-dependent processes. We previously demonstrated that AT2R-mediated effects involve inhibition of the RhoA/Rho kinase pathway.

Up-regulation of cardiac nitric oxide synthase 1-derived nitric oxide after myocardial infarction in senescent rats.

Nitric oxide (NO) has been implicated in the development of heart failure, although the source, significance, and functional role of the different NO synthase (NOS) isoforms in this pathology are controversial. The presence of a neuronal-type NOS isoform (NOS1) in the cardiac sarcoplasmic reticulum has been recently discovered, leading to the hypothesis that NOS1-derived NO may notably alter myocardial inotropy. However, the regulation and role(s) of NOS1 in cardiac diseases remain to be determined.

Intraluminal pressure increases vascular neuronal nitric oxide synthase expression.

Background: Development of high blood pressure (BP) is associated with an increased expression of neuronal nitric oxide synthase (nNOS) in vascular smooth muscle cells.

Methods: We investigated whether or not changes in intraluminal pressure affect nNOS expression in carotid arteries of normotensive rats. Expression of nNOS and other NOS isoforms was determined by Western blot analysis in rat carotid arteries maintained up to 24 h at different levels of intraluminal pressure in an organ culture system.